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研究生:吳芳儒
研究生(外文):Fang-Ju Wu
論文名稱:探討骨形成蛋白-8之訊息傳遞與其在睪丸上的功能
論文名稱(外文):Characterization of the signalings and testicular functions of bone morphogenetic protein 8
指導教授:羅清維
指導教授(外文):Ching-Wei Luo
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生命科學系暨基因體科學研究所
學門:生命科學學門
學類:生物訊息學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:英文
論文頁數:101
中文關鍵詞:骨形成蛋白男性不孕雄性生殖精原母細胞
外文關鍵詞:BMPmale infertilitymale reproductionspermatogonia
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已知在bone morphogenetic protein 8A (Bmp8a) 或 bone morphogenetic protein 8B (Bmp8b) 基因上的缺失會導致雄性小鼠在幼年期時就出現生殖細胞嚴重減少的情形,並造成雄性小鼠生育力下降。然而,我們對於BMP8下游的訊息傳遞路徑以及其如何影響睪丸功能仍然一無所知。在本篇論文的研究中,我們發現BMP8蛋白在幼年雄性小鼠中主要表現在精原母細胞,並且其中以Bmp8a基因的相對表現量高於Bmp8b基因。接著,藉由表現出具有生物活性的BMP8重組蛋白進行實驗,我們意外地發現到在多種細胞株以及初代培養的精原母細胞上,BMP8不僅僅能活化SMAD1/5/8路徑,也能夠活化SMAD2/3路徑。我們發現在未分化的精原母細胞中,BMP8能透過第一型受體ALK5與第二型受體ACVR2A、ACVR2B或TGFBR2所形成的受體複合物活化SMAD2/3路徑,進而造成精原母細胞生長;而另一方面,BMP8也能透過第一型受體ALK3與第二型受體ACVR2A或BMPR2形成的受體複合物活化SMAD1/5/8路徑,進而促成精原母細胞分化。而上述實驗中所發現到的BMP8功能,也能夠在睪丸組織培養過程中得到印證。我們發現到外加BMP8 的睪丸組織能夠觀察到更多精原母細胞處在生長及分化的階段。除此之外,外加BMP8的睪丸組織能夠在培養的過程中更早產生能夠使卵受精的單倍染色體生殖細胞。總結以上結果,我們發現BMP8能夠同時活化的SMAD1/5/8路徑與SMAD2/3路徑,並且藉由這兩條路徑促進精原母細胞生長與分化。而BMP8這樣的雙重功能有機會能夠運用在男性不孕症的治療上。
Although genetic deletion in either of the genes encoding bone morphogenetic protein 8A or 8B (Bmp8a or Bmp8b) causes severe loss of germ cells postnatally and impairs fertility in male mice, the detailed signalings and functions of BMP8 in the testis have not yet been clarified. In the neonatal mouse testis, we found that BMP8 was mainly expressed in spermatogonia, in which the expression level of Bmp8a was relatively higher than that of Bmp8b. Using the advantage provided by the bio-potent BMP8 recombinant proteins we generated, we surprisingly found that BMP8 activated not only SMAD1/5/8 signaling but also SMAD2/3 signaling in various cell lines and primary spermatogonia. In undifferentiated spermatogonia, we found that BMP8 activated SMAD2/3 signaling, mediated through the receptor complexes formed by type I receptor ALK5 and type II receptor ACVR2A, ACVR2B or TGFBR2, to promote the proliferation of spermatogonia. On the other hand, BMP8 activated SMAD1/5/8 signaling, mediated through the receptor complexes formed by type I receptor ALK3 and type II receptor ACVR2A or BMPR2, to direct the subsequent differentiation of spermatogonia. With the above capabilities, BMP8 treatment greatly promoted the spermatogenic progression in cultured testis explants by showing increases in both proliferating and differentiating spermatogonia. Moreover, in the presence of BMP8, post-meiotic germ cells appeared earlier in cultured explants and the resulting round spermatids were functionally competent for fertilization. Thus, these results demonstrate that BMP8 can stimulate signaling through both SMAD1/5/8 and SMAD2/3 and suggest that the dual roles of BMP8 in promoting proliferation and differentiation of spermatogonia may be exploited clinically for treating male infertility.
CONTENTS
致謝 i
摘要 ii
ABSTRACT iii
ABBREVIATION iv
CONTENTS v
FIGURE CONTENTS viii
TABLE CONTENTS x
1. INTRODUCTION 1
1-1. Overview of spermatogenesis 1
1-1-1. Steps of spermatogenesis 1
1-1-2. Characteristics and classification of spermatogonia 2
1-1-3. Cell fate decision of SSCs 4
1-2. Transforming growth factor-β (TGF-) superfamily 5
1-2-1. The peptide structure of the TGF-β superfamily members 6
1-2-2. Signal transduction of TGF- superfamily 6
1-3. The roles of TGF- superfamily in spermatogenesis 8
1-3-1. Activin and inhibin 9
1-3-2. TGF-β 9
1-3-3. BMPs 10
1-3-4. Nodal 10
1-3-5. GDNF 11
1-4. BMP8A and BMP8B 11
1-4-1. BMP8A and BMP8B in spermatogenesis and testis integrity 11
1-4-2. Other physiological roles of BMP8A and BMP8B 12
1-5. Objectives 13
2. MATERIALS AND METHODS 14
2-1. Recombinant proteins, antibodies, and chemicals 14
2-2. Animal use 15
2-3. Cell culture 15
2-4. Testis explant culture 15
2-5. Constructs, expression, and protein purification 15
2-6. Immunoblotting and pull-down assay 17
2-7. Luciferase reporter assay 18
2-8. cDNA preparation, reverse transcription and qPCR analysis 19
2-9. Magnetic-activated cell sorting (MACS) and culture of undifferentiated spermatogonia 20
2-10. Immunohistochemical staining 20
2-11. Immunocytochemcal staining 21
2-12. Flow cytometry for DNA ploidy analysis 22
2-13. Round spermatid injection (ROSI) 22
2-14. PCR genotyping 23
2-15. Statistical analysis 23
3. RESULTS 24
3-1. Production of bioactive recombinant BMP8 proteins 24
3-2. Stimulation of both SMAD1/5/8 and SMAD2/3 pathways by BMP8 proteins 25
3-3. Identification of the receptor complexes used by BMP8 25
3-4. The expression of BMP8 in the testis 27
3-5. The receptor identities of BMP8 in the testis 28
3-6. BMP8 treatment promotes the cell division of spermatogonia 29
3-7. BMP8 treatment promotes the differentiation of spermatogonia 30
3-8. BMP8 treatment enhances the production of meiotic germ cells in neonatal testis explants 31
4. DISCUSSION 34
4-1. Evolutionary view of BMP8 in male infertility 34
4-2. Conflicts about BMP8 downstream signaling pathway 35
4-3. Noncanonical SMAD activation by TGF- superfamily members 36
4-4. Regulation of BMP8 signaling in spermatogenesis 39
4-5. Future perspectives 40
5. REFERENCES 43
6. FIGURES 58
7. TABLES 97

FIGURE CONTENTS
Fig. 1 Schematic representation of the BMP8-expressing constructs. 58
Fig. 2 Detection of recombinant BMP8 proteins. 59
Fig. 3 Bioactivity tests of recombinant BMP8 proteins. 60
Fig. 4 Dose-dependent activation of BRE- and CAGA-luciferase reporters by purified recombinant BMP8A or BMP8B in HEK-293T cells. 61
Fig. 5 BMP8A induces phosphorylation of SMAD1/5/8 and SMAD2/3 in HEK-293T cells. 62
Fig. 6 Dose-dependent activation of the BRE- and CAGA-luciferase reporters by BMP8A in P19 cells. 63
Fig. 7 BMP8A induces phosphorylation of SMAD1/5/8 and SMAD2/3 in P19 cells. 64
Fig. 8 Chimeric hBMP4 and recombinant hBMP10 do not activate CAGA-driven reporter in HEK-293T cells. 65
Fig. 9 Overexpression of type I receptor ALK3, ALK4, ALK5 or ALK6 enhances BMP8A-mediated reporter signals in HEK-293T cells. 66
Fig. 10 Knockdown of ALK3, ALK4, ALK5 or ALK6 suppresses BMP8A-mediated reporter signals in HEK-293T cells. 67
Fig. 11 The transcript abundance of type II receptors in HEK-293T cells. 68
Fig. 12 Overexpression of AMHR2 does not enhance BMP8A-induced BRE-driven reporter activities in HEK-293T cells. 69
Fig. 13 Knockdown of type II receptor ACVR2A, ACVR2B, BMPR2 or TGFBR2 suppresses BMP8A-mediated reporter signals in HEK-293T cells. 70
Fig. 14 Direct interaction between type ІІ receptor TGFBR2 and BMP8A in the pull-down assay. 71
Fig. 15 Direct interaction between type І receptor ALK3 or ALK5 and BMP8A in the pull-down assay. 72
Fig. 16 Interaction between type ІІ receptor TGFBR2, type І receptor ALK5 and BMP8A in the pull-down assay. 73
Fig. 17 Impairment of BMP8A-induced reporter signals by TGFBR2-Fc or ALK3-Fc chimera proteins. 74
Fig. 18 The proposed model of BMP8-mediated signal transduction. 76
Fig. 19 Expression of BMP8 protein in the mouse testis. 77
Fig. 20 The transcript abundance of bmp8a and bmp8b in MACS-separated Thy1+ and Thy1- testicular cells. 78
Fig. 21 Localization of the BMP8 protein signal in the neonatal mouse testis. 79
Fig. 22 Co-staining of BMP8 and GATA4 in the neonatal mouse testis. 80
Fig. 23 BMP8A treatment induces SMAD phosphorylation in primary spermatogonia. 81
Fig. 24 The transcript abundance of potential receptors for BMP8 in undifferentiated spermatogonia. 82
Fig. 25 Knockdown of Acvr2a, Acvr2b, Bmpr2, Tgfbr2, Alk3 or Alk5 impairs BMP8-mediated SMAD phosphorylation. 83
Fig. 26 BMP8A treatment promotes the division of spermatogonia. 84
Fig. 27 BMP8A upregulates Ccnd1 and Ccne1 transcripts but does not affect Bcl2 and Bax expression in spermatogonia. 85
Fig. 28 The effect of BMP8A treatment on the expression levels of self-renewal-related genes in spermatogonia. 86
Fig. 29 BMP8A treatment increases cKIT protein amount in spermatogonia. 87
Fig. 30 BMP8A can upregulate the transcripts of cKit and Sohlh2, but not Stra8, in spermatogonia. 88
Fig. 31 BMP8A treatment promotes cell proliferation in the testis explants. 89
Fig. 32 BMP8A treatment promotes spermatogonia proliferation in the cultured testis explants. 90
Fig. 33 BMP8A treatment promotes spermatogonia differentiation in the cultured testis explants. 91
Fig. 34 BMP8A treatment facilitates haploid cell formation in the testis explant culture. 92
Fig. 35 BMP8A facilities meiotic germ cell formation in the testis explant culture. 93
Fig. 36 BMP8A treatment increases the expression of several meiotic and post-meiotic markers in the testis explant culture. 94
Fig. 37 The morphology and reproductive capacity of round spermatids retrieved from the testis explants with BMP8A treatment. 95


TABLE CONTENTS
Table 1. Fertilization and development of zygotes after ROSI. 97
Table 2. shRNA clone list 98
Table 3. Primers used for plasmid construction. 99
Table 4. Primers used for qPCR. 100
1. Adler, I.D. (1996). Comparison of the duration of spermatogenesis between male rodents and humans. Mutat Res 352, 169-172.
2. Agarwal, A., Mulgund, A., Hamada, A., and Chyatte, M.R. (2015). A unique view on male infertility around the globe. Reprod Biol Endocrinol 13, 37.
3. Bache, I., Assche, E.V., Cingoz, S., Bugge, M., Tumer, Z., Hjorth, M., Lundsteen, C., Lespinasse, J., Winther, K., Niebuhr, A., Kalscheuer, V., Liebaers, I., Bonduelle, M., Tournaye, H., Ayuso, C., Barbi, G., Blennow, E., Bourrouillou, G., Brondum-Nielsen, K., Bruun-Petersen, G., Croquette, M.F., Dahoun, S., Dallapiccola, B., Davison, V., Delobel, B., Duba, H.C., Duprez, L., Ferguson-Smith, M., Fitzpatrick, D.R., Grace, E., Hansmann, I., Hulten, M., Jensen, P.K., Jonveaux, P., Kristoffersson, U., Lopez-Pajares, I., McGowan-Jordan, J., Murken, J., Orera, M., Parkin, T., Passarge, E., Ramos, C., Rasmussen, K., Schempp, W., Schubert, R., Schwinger, E., Shabtai, F., Smith, K., Stallings, R., Stefanova, M., Tranebjerg, L., Turleau, C., van der Hagen, C.B., Vekemans, M., Vokac, N.K., Wagner, K., Wahlstroem, J., Zelante, L., and Tommerup, N. (2004). An excess of chromosome 1 breakpoints in male infertility. Eur J Hum Genet 12, 993-1000.
4. Behringer, R.R., Finegold, M.J., and Cate, R.L. (1994). Mullerian-inhibiting substance function during mammalian sexual development. Cell 79, 415-425.
5. Bellve, A.R., Millette, C.F., Bhatnagar, Y.M., and O'Brien, D.A. (1977). Dissociation of the mouse testis and characterization of isolated spermatogenic cells. J Histochem Cytochem 25, 480-494.
6. Bermudez, D., Escalier, D., Gallo, J.M., Viellefond, A., Rius, F., Perez de Vargas, I., and Schrevel, J. (1994). Proacrosin as a marker of meiotic and post-meiotic germ cell differentiation: quantitative assessment of human spermatogenesis with a monoclonal antibody. J Reprod Fertil 100, 567-575.
7. Boitani, C., Stefanini, M., Fragale, A., and Morena, A.R. (1995). Activin stimulates Sertoli cell proliferation in a defined period of rat testis development. Endocrinology 136, 5438-5444.
8. Buageaw, A., Sukhwani, M., Ben-Yehudah, A., Ehmcke, J., Rawe, V.Y., Pholpramool, C., Orwig, K.E., and Schlatt, S. (2005). GDNF family receptor alpha1 phenotype of spermatogonial stem cells in immature mouse testes. Biol Reprod 73, 1011-1016.
9. Chandley, A.C., McBeath, S., Speed, R.M., Yorston, L., and Hargreave, T.B. (1987). Pericentric inversion in human chromosome 1 and the risk for male sterility. J Med Genet 24, 325-334.
10. Chiarini-Garcia, H., and Russell, L.D. (2001). High-resolution light microscopic characterization of mouse spermatogonia. Biol Reprod 65, 1170-1178.
11. Clermont, Y., and Leblond, C.P. (1953). Renewal of spermatogonia in the rat. Am J Anat 93, 475-501.
12. Conidi, A., Cazzola, S., Beets, K., Coddens, K., Collart, C., Cornelis, F., Cox, L., Joke, D., Dobreva, M.P., Dries, R., Esguerra, C., Francis, A., Ibrahimi, A., Kroes, R., Lesage, F., Maas, E., Moya, I., Pereira, P.N., Stappers, E., Stryjewska, A., van den Berghe, V., Vermeire, L., Verstappen, G., Seuntjens, E., Umans, L., Zwijsen, A., and Huylebroeck, D. (2011). Few Smad proteins and many Smad-interacting proteins yield multiple functions and action modes in TGFbeta/BMP signaling in vivo. Cytokine Growth Factor Rev 22, 287-300.
13. Conlon, F.L., Lyons, K.M., Takaesu, N., Barth, K.S., Kispert, A., Herrmann, B., and Robertson, E.J. (1994). A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse. Development 120, 1919-1928.
14. Costoya, J.A., Hobbs, R.M., Barna, M., Cattoretti, G., Manova, K., Sukhwani, M., Orwig, K.E., Wolgemuth, D.J., and Pandolfi, P.P. (2004). Essential role of Plzf in maintenance of spermatogonial stem cells. Nat Genet 36, 653-659.
15. de Rooij, D.G. (2001). Proliferation and differentiation of spermatogonial stem cells. Reproduction 121, 347-354.
16. Dennler, S., Itoh, S., Vivien, D., ten Dijke, P., Huet, S., and Gauthier, J.M. (1998). Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J 17, 3091-3100.
17. Dias, V., Meachem, S., Rajpert-De Meyts, E., McLachlan, R., Manuelpillai, U., and Loveland, K.L. (2008). Activin receptor subunits in normal and dysfunctional adult human testis. Hum Reprod 23, 412-420.
18. Dudley, B., Palumbo, C., Nalepka, J., and Molyneaux, K. (2010). BMP signaling controls formation of a primordial germ cell niche within the early genital ridges. Dev Biol 343, 84-93.
19. Feng, X.H., and Derynck, R. (2005). Specificity and versatility in tgf-beta signaling through Smads. Annu Rev Cell Dev Biol 21, 659-693.
20. Ferlin, A., Moro, E., Garolla, A., and Foresta, C. (1999). Human male infertility and Y chromosome deletions: role of the AZF-candidate genes DAZ, RBM and DFFRY. Hum Reprod 14, 1710-1716.
21. Foresta, C., Moro, E., and Ferlin, A. (2001). Y chromosome microdeletions and alterations of spermatogenesis. Endocr Rev 22, 226-239.
22. Gartner, L.P. (2007). Textbook of Histology, 3rd Edition. 21, 559-582.
23. Gautier, C., Levacher, C., Avallet, O., Vigier, M., Rouiller-Fabre, V., Lecerf, L., Saez, J., and Habert, R. (1994). Immunohistochemical localization of transforming growth factor-beta 1 in the fetal and neonatal rat testis. Mol Cell Endocrinol 99, 55-61.
24. Ge, G., Hopkins, D.R., Ho, W.B., and Greenspan, D.S. (2005). GDF11 forms a bone morphogenetic protein 1-activated latent complex that can modulate nerve growth factor-induced differentiation of PC12 cells. Mol Cell Biol 25, 5846-5858.
25. Gentry, L.E., Lioubin, M.N., Purchio, A.F., and Marquardt, H. (1988). Molecular events in the processing of recombinant type 1 pre-pro-transforming growth factor beta to the mature polypeptide. Mol Cell Biol 8, 4162-4168.
26. Gesualdi, S.C., and Haerry, T.E. (2007). Distinct signaling of Drosophila Activin/TGF-beta family members. Fly (Austin) 1, 212-221.
27. Goldberg, E., Eddy, E.M., Duan, C., and Odet, F. (2010). LDHC: the ultimate testis-specific gene. J Androl 31, 86-94.
28. Greenbaum, M.P., Iwamori, T., Buchold, G.M., and Matzuk, M.M. (2011). Germ cell intercellular bridges. Cold Spring Harb Perspect Biol 3, a005850.
29. Greenwald, J., Fischer, W.H., Vale, W.W., and Choe, S. (1999). Three-finger toxin fold for the extracellular ligand-binding domain of the type II activin receptor serine kinase. Nat Struct Biol 6, 18-22.
30. Greenwald, J., Groppe, J., Gray, P., Wiater, E., Kwiatkowski, W., Vale, W., and Choe, S. (2003). The BMP7/ActRII extracellular domain complex provides new insights into the cooperative nature of receptor assembly. Mol Cell 11, 605-617.
31. Gregory, S.J., and Kaiser, U.B. (2004). Regulation of gonadotropins by inhibin and activin. Semin Reprod Med 22, 253-267.
32. Griswold, M.D., Bishop, P.D., Kim, K.H., Ping, R., Siiteri, J.E., and Morales, C. (1989). Function of vitamin A in normal and synchronized seminiferous tubules. Ann N Y Acad Sci 564, 154-172.
33. Groppe, J., Hinck, C.S., Samavarchi-Tehrani, P., Zubieta, C., Schuermann, J.P., Taylor, A.B., Schwarz, P.M., Wrana, J.L., and Hinck, A.P. (2008). Cooperative assembly of TGF-beta superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding. Mol Cell 29, 157-168.
34. Handel, M.A., Eppig, J.J., and Schimenti, J.C. (2014). Applying "gold standards" to in-vitro-derived germ cells. Cell 157, 1257-1261.
35. Hayashi, K., Yoshida, K., and Matsui, Y. (2005). A histone H3 methyltransferase controls epigenetic events required for meiotic prophase. Nature 438, 374-378.
36. He, Z., Jiang, J., Kokkinaki, M., and Dym, M. (2009). Nodal signaling via an autocrine pathway promotes proliferation of mouse spermatogonial stem/progenitor cells through Smad2/3 and Oct-4 activation. Stem Cells 27, 2580-2590.
37. He, Z., Jiang, J., Kokkinaki, M., Golestaneh, N., Hofmann, M.C., and Dym, M. (2008). Gdnf upregulates c-Fos transcription via the Ras/Erk1/2 pathway to promote mouse spermatogonial stem cell proliferation. Stem Cells 26, 266-278.
38. Hermann, B.P., Phillips, B.T., and Orwig, K.E. (2011). The elusive spermatogonial stem cell marker? Biol Reprod 85, 221-223.
39. Herpin, A., Lelong, C., and Favrel, P. (2004). Transforming growth factor-beta-related proteins: an ancestral and widespread superfamily of cytokines in metazoans. Dev Comp Immunol 28, 461-485.
40. Holtzhausen, A., Golzio, C., How, T., Lee, Y.H., Schiemann, W.P., Katsanis, N., and Blobe, G.C. (2014). Novel bone morphogenetic protein signaling through Smad2 and Smad3 to regulate cancer progression and development. FASEB J 28, 1248-1267.
41. Huckins, C. (1971). The spermatogonial stem cell population in adult rats. I. Their morphology, proliferation and maturation. Anat Rec 169, 533-557.
42. Jiang, M.S., Liang, L.F., Wang, S., Ratovitski, T., Holmstrom, J., Barker, C., and Stotish, R. (2004). Characterization and identification of the inhibitory domain of GDF-8 propeptide. Biochem Biophys Res Commun 315, 525-531.
43. Jurisicova, A., Lopes, S., Meriano, J., Oppedisano, L., Casper, R.F., and Varmuza, S. (1999). DNA damage in round spermatids of mice with a targeted disruption of the Pp1cgamma gene and in testicular biopsies of patients with non-obstructive azoospermia. Mol Hum Reprod 5, 323-330.
44. Kawase, E., Wong, M.D., Ding, B.C., and Xie, T. (2004). Gbb/Bmp signaling is essential for maintaining germline stem cells and for repressing bam transcription in the Drosophila testis. Development 131, 1365-1375.
45. Keller, S., Nickel, J., Zhang, J.L., Sebald, W., and Mueller, T.D. (2004). Molecular recognition of BMP-2 and BMP receptor IA. Nat Struct Mol Biol 11, 481-488.
46. Kim, J.S., Chae, J.H., Cheon, Y.P., and Kim, C.G. (2016). Reciprocal localization of transcription factors YY1 and CP2c in spermatogonial stem cells and their putative roles during spermatogenesis. Acta Histochem 118, 685-692.
47. Kimura, Y., and Yanagimachi, R. (1995). Mouse oocytes injected with testicular spermatozoa or round spermatids can develop into normal offspring. Development 121, 2397-2405.
48. Kingsley, D.M. (1994). The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms. Genes Dev 8, 133-146.
49. Korchynskyi, O., and ten Dijke, P. (2002). Identification and functional characterization of distinct critically important bone morphogenetic protein-specific response elements in the Id1 promoter. J Biol Chem 277, 4883-4891.
50. Kretzschmar, M., and Massague, J. (1998). SMADs: mediators and regulators of TGF-beta signaling. Curr Opin Genet Dev 8, 103-111.
51. Kubota, H., Avarbock, M.R., and Brinster, R.L. (2004). Culture conditions and single growth factors affect fate determination of mouse spermatogonial stem cells. Biol Reprod 71, 722-731.
52. Kubota, H., and Brinster, R.L. (2008). Culture of rodent spermatogonial stem cells, male germline stem cells of the postnatal animal. Methods Cell Biol 86, 59-84.
53. Kulkarni, A.B., Huh, C.G., Becker, D., Geiser, A., Lyght, M., Flanders, K.C., Roberts, A.B., Sporn, M.B., Ward, J.M., and Karlsson, S. (1993). Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci U S A 90, 770-774.
54. Kumar, N., and Singh, A.K. (2015). Trends of male factor infertility, an important cause of infertility: A review of literature. J Hum Reprod Sci 8, 191-196.
55. Lawson, K.A., Dunn, N.R., Roelen, B.A., Zeinstra, L.M., Davis, A.M., Wright, C.V., Korving, J.P., and Hogan, B.L. (1999). Bmp4 is required for the generation of primordial germ cells in the mouse embryo. Genes Dev 13, 424-436.
56. Lebrun, J.J., and Vale, W.W. (1997). Activin and inhibin have antagonistic effects on ligand-dependent heteromerization of the type I and type II activin receptors and human erythroid differentiation. Mol Cell Biol 17, 1682-1691.
57. Leighton, M., and Kadler, K.E. (2003). Paired basic/Furin-like proprotein convertase cleavage of Pro-BMP-1 in the trans-Golgi network. J Biol Chem 278, 18478-18484.
58. Lilienbaum, A., Sage, J., Memet, S., Rassoulzadegan, M., Cuzin, F., and Israel, A. (2000). NF-kappa B is developmentally regulated during spermatogenesis in mice. Dev Dyn 219, 333-340.
59. Lin, T., Calkins, J.K., Morris, P.L., Vale, W., and Bardin, C.W. (1989). Regulation of Leydig cell function in primary culture by inhibin and activin. Endocrinology 125, 2134-2140.
60. Long, S., Truong, L., Bennett, K., Phillips, A., Wong-Staal, F., and Ma, H. (2006). Expression, purification, and renaturation of bone morphogenetic protein-2 from Escherichia coli. Protein Expr Purif 46, 374-378.
61. Loveland, K.L., and Schlatt, S. (1997). Stem cell factor and c-kit in the mammalian testis: lessons originating from Mother Nature's gene knockouts. J Endocrinol 153, 337-344.
62. Lui, W.Y., Lee, W.M., and Cheng, C.Y. (2001). Transforming growth factor-beta3 perturbs the inter-Sertoli tight junction permeability barrier in vitro possibly mediated via its effects on occludin, zonula occludens-1, and claudin-11. Endocrinology 142, 1865-1877.
63. Ma, W., Horvath, G.C., Kistler, M.K., and Kistler, W.S. (2008). Expression patterns of SP1 and SP3 during mouse spermatogenesis: SP1 down-regulation correlates with two successive promoter changes and translationally compromised transcripts. Biol Reprod 79, 289-300.
64. Massague, J. (1990). The transforming growth factor-beta family. Annu Rev Cell Biol 6, 597-641.
65. Massague, J. (1998). TGF-beta signal transduction. Annu Rev Biochem 67, 753-791.
66. Massague, J. (2012). TGFbeta signalling in context. Nat Rev Mol Cell Biol 13, 616-630.
67. Matzuk, M.M., Kumar, T.R., Vassalli, A., Bickenbach, J.R., Roop, D.R., Jaenisch, R., and Bradley, A. (1995). Functional analysis of activins during mammalian development. Nature 374, 354-356.
68. Mazerbourg, S., Sangkuhl, K., Luo, C.W., Sudo, S., Klein, C., and Hsueh, A.J. (2005). Identification of receptors and signaling pathways for orphan bone morphogenetic protein/growth differentiation factor ligands based on genomic analyses. J Biol Chem 280, 32122-32132.
69. Meehan, T., Schlatt, S., O'Bryan, M.K., de Kretser, D.M., and Loveland, K.L. (2000). Regulation of germ cell and Sertoli cell development by activin, follistatin, and FSH. Dev Biol 220, 225-237.
70. Meng, X., Lindahl, M., Hyvonen, M.E., Parvinen, M., de Rooij, D.G., Hess, M.W., Raatikainen-Ahokas, A., Sainio, K., Rauvala, H., Lakso, M., Pichel, J.G., Westphal, H., Saarma, M., and Sariola, H. (2000). Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. Science 287, 1489-1493.
71. Meschede, D., Froster, U.G., Bergmann, M., and Nieschlag, E. (1994). Familial pericentric inversion of chromosome 1 (p34q23) and male infertility with stage specific spermatogenic arrest. J Med Genet 31, 573-575.
72. Monesi, V. (1962). Autoradiographic study of DNA synthesis and the cell cycle in spermatogonia and spermatocytes of mouse testis using tritiated thymidine. J Cell Biol 14, 1-18.
73. Moreno, S.G., Attali, M., Allemand, I., Messiaen, S., Fouchet, P., Coffigny, H., Romeo, P.H., and Habert, R. (2010). TGFbeta signaling in male germ cells regulates gonocyte quiescence and fertility in mice. Dev Biol 342, 74-84.
74. Moretti, C., Vaiman, D., Tores, F., and Cocquet, J. (2016). Expression and epigenomic landscape of the sex chromosomes in mouse post-meiotic male germ cells. Epigenetics Chromatin 9, 47.
75. Mueller, T.D., and Nickel, J. (2012). Promiscuity and specificity in BMP receptor activation. FEBS Lett 586, 1846-1859.
76. Nakagawa, T., Nabeshima, Y., and Yoshida, S. (2007). Functional identification of the actual and potential stem cell compartments in mouse spermatogenesis. Dev Cell 12, 195-206.
77. Neumann, J.C., Chandler, G.L., Damoulis, V.A., Fustino, N.J., Lillard, K., Looijenga, L., Margraf, L., Rakheja, D., and Amatruda, J.F. (2011). Mutation in the type IB bone morphogenetic protein receptor Alk6b impairs germ-cell differentiation and causes germ-cell tumors in zebrafish. Proc Natl Acad Sci U S A 108, 13153-13158.
78. O'Donnell, L. (2014). Mechanisms of spermiogenesis and spermiation and how they are disturbed. Spermatogenesis 4, e979623.
79. Oakberg, E.F. (1971). Spermatogonial stem-cell renewal in the mouse. Anat Rec 169, 515-531.
80. Oatley, J.M., Avarbock, M.R., and Brinster, R.L. (2007). Glial cell line-derived neurotrophic factor regulation of genes essential for self-renewal of mouse spermatogonial stem cells is dependent on Src family kinase signaling. J Biol Chem 282, 25842-25851.
81. Oatley, J.M., and Brinster, R.L. (2008). Regulation of spermatogonial stem cell self-renewal in mammals. Annu Rev Cell Dev Biol 24, 263-286.
82. Oatley, J.M., Oatley, M.J., Avarbock, M.R., Tobias, J.W., and Brinster, R.L. (2009). Colony stimulating factor 1 is an extrinsic stimulator of mouse spermatogonial stem cell self-renewal. Development 136, 1191-1199.
83. Ogonuki, N., Mochida, K., Inoue, K., Matsuda, J., Yamamoto, Y., Takano, K., and Ogura, A. (2003). Fertilization of oocytes and birth of normal pups following intracytoplasmic injection with spermatids in mastomys (Praomys coucha). Biol Reprod 68, 1821-1827.
84. Ohinata, Y., Ohta, H., Shigeta, M., Yamanaka, K., Wakayama, T., and Saitou, M. (2009). A signaling principle for the specification of the germ cell lineage in mice. Cell 137, 571-584.
85. Olaso, R., Gautier, C., Levacher, C., Durand, P., Saez, J., and Habert, R. (1997). The immunohistochemical localization of transforming growth factor-beta 2 in the fetal and neonatal rat testis. Mol Cell Endocrinol 126, 165-172.
86. Olaso, R., Pairault, C., Boulogne, B., Durand, P., and Habert, R. (1998). Transforming growth factor beta1 and beta2 reduce the number of gonocytes by increasing apoptosis. Endocrinology 139, 733-740.
87. Olaso, R., Pairault, C., Saez, J.M., and Habert, R. (1999). Transforming growth factor beta3 in the fetal and neonatal rat testis: immunolocalization and effect on fetal Leydig cell function. Histochem Cell Biol 112, 247-254.
88. Olesen, C., Hansen, C., Bendsen, E., Byskov, A.G., Schwinger, E., Lopez-Pajares, I., Jensen, P.K., Kristoffersson, U., Schubert, R., Van Assche, E., Wahlstroem, J., Lespinasse, J., and Tommerup, N. (2001). Identification of human candidate genes for male infertility by digital differential display. Mol Hum Reprod 7, 11-20.
89. Oulad-Abdelghani, M., Bouillet, P., Decimo, D., Gansmuller, A., Heyberger, S., Dolle, P., Bronner, S., Lutz, Y., and Chambon, P. (1996). Characterization of a premeiotic germ cell-specific cytoplasmic protein encoded by Stra8, a novel retinoic acid-responsive gene. J Cell Biol 135, 469-477.
90. Ozkaynak, E., Schnegelsberg, P.N., Jin, D.F., Clifford, G.M., Warren, F.D., Drier, E.A., and Oppermann, H. (1992). Osteogenic protein-2. A new member of the transforming growth factor-beta superfamily expressed early in embryogenesis. J Biol Chem 267, 25220-25227.
91. Pellegrini, M., Grimaldi, P., Rossi, P., Geremia, R., and Dolci, S. (2003). Developmental expression of BMP4/ALK3/SMAD5 signaling pathway in the mouse testis: a potential role of BMP4 in spermatogonia differentiation. J Cell Sci 116, 3363-3372.
92. Phillips, B.T., Gassei, K., and Orwig, K.E. (2010). Spermatogonial stem cell regulation and spermatogenesis. Philos Trans R Soc Lond B Biol Sci 365, 1663-1678.
93. Puglisi, R., Montanari, M., Chiarella, P., Stefanini, M., and Boitani, C. (2004). Regulatory role of BMP2 and BMP7 in spermatogonia and Sertoli cell proliferation in the immature mouse. Eur J Endocrinol 151, 511-520.
94. Renlund, N., O'Neill, F.H., Zhang, L., Sidis, Y., and Teixeira, J. (2007). Activin receptor-like kinase-2 inhibits activin signaling by blocking the binding of activin to its type II receptor. J Endocrinol 195, 95-103.
95. Roosen-Runge, E.C., and Giesel, L.O., Jr. (1950). Quantitative studies on spermatogenesis in the albino rat. Am J Anat 87, 1-30.
96. Rossi, P., Dolci, S., Albanesi, C., Grimaldi, P., Ricca, R., and Geremia, R. (1993). Follicle-stimulating hormone induction of steel factor (SLF) mRNA in mouse Sertoli cells and stimulation of DNA synthesis in spermatogonia by soluble SLF. Dev Biol 155, 68-74.
97. Sanford, L.P., Ormsby, I., Gittenberger-de Groot, A.C., Sariola, H., Friedman, R., Boivin, G.P., Cardell, E.L., and Doetschman, T. (1997). TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes. Development 124, 2659-2670.
98. Sasaki, H., and Matsui, Y. (2008). Epigenetic events in mammalian germ-cell development: reprogramming and beyond. Nat Rev Genet 9, 129-140.
99. Sato, T., Katagiri, K., Gohbara, A., Inoue, K., Ogonuki, N., Ogura, A., Kubota, Y., and Ogawa, T. (2011). In vitro production of functional sperm in cultured neonatal mouse testes. Nature 471, 504-507.
100. Sato, T., Yokonishi, T., Komeya, M., Katagiri, K., Kubota, Y., Matoba, S., Ogonuki, N., Ogura, A., Yoshida, S., and Ogawa, T. (2012). Testis tissue explantation cures spermatogenic failure in c-Kit ligand mutant mice. Proc Natl Acad Sci U S A 109, 16934-16938.
101. Schrans-Stassen, B.H., Saunders, P.T., Cooke, H.J., and de Rooij, D.G. (2001). Nature of the spermatogenic arrest in Dazl -/- mice. Biol Reprod 65, 771-776.
102. Schultz, R., Isola, J., Parvinen, M., Honkaniemi, J., Wikstrom, A.C., Gustafsson, J.A., and Pelto-Huikko, M. (1993). Localization of the glucocorticoid receptor in testis and accessory sexual organs of male rat. Mol Cell Endocrinol 95, 115-120.
103. Settle, S., Marker, P., Gurley, K., Sinha, A., Thacker, A., Wang, Y., Higgins, K., Cunha, G., and Kingsley, D.M. (2001). The BMP family member Gdf7 is required for seminal vesicle growth, branching morphogenesis, and cytodifferentiation. Dev Biol 234, 138-150.
104. Shirakata, Y., Hiradate, Y., Inoue, H., Sato, E., and Tanemura, K. (2014). Histone h4 modification during mouse spermatogenesis. J Reprod Dev 60, 383-387.
105. Shivdasani, A.A., and Ingham, P.W. (2003). Regulation of stem cell maintenance and transit amplifying cell proliferation by tgf-beta signaling in Drosophila spermatogenesis. Curr Biol 13, 2065-2072.
106. Song, H.W., and Wilkinson, M.F. (2012). In vitro spermatogenesis: A long journey to get tails. Spermatogenesis 2, 238-244.
107. Wang, H., Yuan, Q., Sun, M., Niu, M., Wen, L., Fu, H., Zhou, F., Chen, Z., Yao, C., Hou, J., Shen, R., Lin, Q., Liu, W., Jia, R., Li, Z., and He, Z. (2017). BMP6 Regulates Proliferation and Apoptosis of Human Sertoli Cells Via Smad2/3 and Cyclin D1 Pathway and DACH1 and TFAP2A Activation. Sci Rep 7, 45298.
108. Wang, S., Wang, X., Wu, Y., and Han, C. (2015). IGF-1R signaling is essential for the proliferation of cultured mouse spermatogonial stem cells by promoting the G2/M progression of the cell cycle. Stem Cells Dev 24, 471-483.
109. Wang, Y., Ho, C.C., Bang, E., Rejon, C.A., Libasci, V., Pertchenko, P., Hebert, T.E., and Bernard, D.J. (2014). Bone morphogenetic protein 2 stimulates noncanonical SMAD2/3 signaling via the BMP type 1A receptor in gonadotrope-like cells: implications for FSH synthesis. Endocrinology 155, 1970-1981.
110. Whittle, A.J., Carobbio, S., Martins, L., Slawik, M., Hondares, E., Vazquez, M.J., Morgan, D., Csikasz, R.I., Gallego, R., Rodriguez-Cuenca, S., Dale, M., Virtue, S., Villarroya, F., Cannon, B., Rahmouni, K., Lopez, M., and Vidal-Puig, A. (2012). BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell 149, 871-885.
111. Wong, T.T., and Collodi, P. (2013). Dorsomorphin promotes survival and germline competence of zebrafish spermatogonial stem cells in culture. PLoS One 8, e71332.
112. Yeh, L.C., Falcon, W.E., Garces, A., and Lee, J.C. (2012). A host-guest relationship in bone morphogenetic protein receptor-II defines specificity in ligand-receptor recognition. Biochemistry 51, 6968-6980.
113. Yelick, P.C., Kwon, Y.H., Flynn, J.F., Borzorgzadeh, A., Kleene, K.C., and Hecht, N.B. (1989). Mouse transition protein 1 is translationally regulated during the postmeiotic stages of spermatogenesis. Mol Reprod Dev 1, 193-200.
114. Ying, Y., Liu, X.M., Marble, A., Lawson, K.A., and Zhao, G.Q. (2000). Requirement of Bmp8b for the generation of primordial germ cells in the mouse. Mol Endocrinol 14, 1053-1063.
115. Ying, Y., Qi, X., and Zhao, G.Q. (2001). Induction of primordial germ cells from murine epiblasts by synergistic action of BMP4 and BMP8B signaling pathways. Proc Natl Acad Sci U S A 98, 7858-7862.
116. Young, J.C., Wakitani, S., and Loveland, K.L. (2015). TGF-beta superfamily signaling in testis formation and early male germline development. Semin Cell Dev Biol 45, 94-103.
117. Zhang, H., Tian, S., Klausen, C., Zhu, H., Liu, R., and Leung, P.C. (2016). Differential activation of noncanonical SMAD2/SMAD3 signaling by bone morphogenetic proteins causes disproportionate induction of hyaluronan production in immortalized human granulosa cells. Mol Cell Endocrinol 428, 17-27.
118. Zhao, G.Q. (2003). Consequences of knocking out BMP signaling in the mouse. Genesis 35, 43-56.
119. Zhao, G.Q., Chen, Y.X., Liu, X.M., Xu, Z., and Qi, X. (2001). Mutation in Bmp7 exacerbates the phenotype of Bmp8a mutants in spermatogenesis and epididymis. Dev Biol 240, 212-222.
120. Zhao, G.Q., Deng, K., Labosky, P.A., Liaw, L., and Hogan, B.L. (1996). The gene encoding bone morphogenetic protein 8B is required for the initiation and maintenance of spermatogenesis in the mouse. Genes Dev 10, 1657-1669.
121. Zhao, G.Q., and Hogan, B.L. (1996). Evidence that mouse Bmp8a (Op2) and Bmp8b are duplicated genes that play a role in spermatogenesis and placental development. Mech Dev 57, 159-168.
122. Zhao, G.Q., and Hogan, B.L. (1997). Evidence that Mothers-against-dpp-related 1 (Madr1) plays a role in the initiation and maintenance of spermatogenesis in the mouse. Mech Dev 61, 63-73.
123. Zhao, G.Q., Liaw, L., and Hogan, B.L. (1998). Bone morphogenetic protein 8A plays a role in the maintenance of spermatogenesis and the integrity of the epididymis. Development 125, 1103-1112.
124. Zhou, Q., and Griswold, M.D. (2008). Regulation of spermatogonia. In StemBook (Cambridge (MA)).
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